4-halo-11beta, 17alpha-dihydroxypregnane-3-20-diones



Patented Apr. 6, 1954 UNITED STATES PATENT OFFICE 4-HALO-'11fi,17oz-DIHYDROXYPR'EGNANE- 3-20-DIONES Robert H. Levin, Kalamazoo Township,.Kalamazoo County, and Barney J. Magerleim'Kalamazoo, Mich., assignorsto The Upjohn Company,

Kalamazoo, M1ch., a corporation of Michigan No Drawing. ApplicationOctober 27, 1952, Serial No. 317,159

3 Claims. (01. 260-39735) wherein X is a halogen of atomic weight from35 to 80 and is selected from chlorine and bromine. The process of thepresent invention involves reacting 11,8,17a-dihydroxypregnane-3;2Odione with a halogenating agent such as, forexample, 25

dichloride, chloroform, carbon tetrachloride and other solvents.

It is an object of the present inventionto provide the novel compounds,4-halo-1'1fl,17a-dihydroxypregnane 3,20 diones. Other objects :01" theinvention will be apparent to one skilled in the art to which thisinvention pertains.

The novel compounds of the present'invention have utility as stable,solid intermediates for the preparation of physiologically activesubstances such as, for example, Kendall's Compound F acetate(11,13,170: dihydroxy-21-'acetoxy-4-pregnene-3,20-dione) and the newcompound 1151170:- dihydroxy-4-pregnene-320-dione. For'this purpose 4halo 115,170; dihydroxypregnane-3,'20- dione is treated with.semicarbazide followed by pyruvic acid. The thus-obtained1-1B,1-7a-dihy droXy-4-pregnene-3,20 dione when reacted with leadtetraaceta'te is productive of Kendalls Compound F acetate.115,17a-dihydroxy-4-pregnene-3,20-dione has a pronounced inhibitingeffect on the secretion of adrenocorticotrophic hormone (ACTH) andtherefore'is of'value in the treatment of diseases where oversecretionof ACTH and adrenal hormones occurs, for example in adrenal hyperplasiaand pituitary basophilism (Cushings disease) 55 The starting compoundfor the present invention is 115,170; dihydroxypregnane-3,20-dione,which is prepared by reacting 17a-hydroxypregmane-3,11,20-trione with analkanediol, preferably a lower-alkane-L2-diol or lower-alkane-l,3-dioLin thepresence of an acid catalyst, reducing the thus-obtainedIZa-hydroXypregnane-S,11,20- trione, 3,20-cyclic diketal with a reducingagent,

hydride or hydrogen in the presence of a, catalyst, and hydrolyzing thethus-obtained 11,8,17u-dlh57- droxypregnane-3,20-dione, 3,20 diketalwith a strong acid to obtain the 11fi,17a-dihydroxypregnane-3,-20-dione.

In carrying out the process of the present invention, 115,170dihydroxypregnane-3,20-dione is dissolved in an organic solvent, suchas, for example, acetic acid, methylene dichloride, chloroform, carbontetrachloride, tertiary butyl alcohol, N,N-dimethylformamide,N,N-dimethylacetamide or other N',N-dialkylacylamides, with acetic acidbeing preferred, and to this solution is added thehalogen, either assuch or as a solution in the same solvent. The product is isolated bypouring the reaction mixture into a cooled sodium chloride solution andseparating the thus-precipitated product from the solution order toavoid any large excess of the halogen in the reaction mixture. In thisway each drop is added as soon as the'previous drop has reacted asindicated by the loss of color. Consequently,

The preferredimolar ratio of 11B,l'la-dihydroxypregnane-- 3,20dione tohalogen is one mole of the steroid acid,. para-toluenesulfonic acid,naphthalenesulionic acid or other like compounds may be used.

The following examples illustrate the process and products of thepresent invention, but are not to be construed as limiting.

PREPARATION 1.-17 oL-HYDROXYPREGNANE-3,11,20-

TBIONE, 3,20-ETHYLENE GLYCOL DIKETAL A solution of 700 milligrams ofl'la-hydroxypregnane-3,1l,20-trione, five milliliters of predistilledethylene glycol, fifty milligrams of paratoluenesulfonic acidmonohydrate and 150 milliliters of benzene was placed in a reactionflask equipped with a reflux condenser and a water trap. The mixture washeated under reflux with stirring for ten hours. Water'which formed wasremoved by co-distillation with benzene and was collected in the watertrap. The reaction mixture was cooled, washed with fifty milliliters ofdilute sodium bicarbonate solution and with water, and then dried andconcentrated to dryness under reduced pressure. The white crystallineresidue was recrystallized repeatedly from ethyl acetate-Skellysolve Bsolution to yield about 600 milligrams of l'la-hydroxypregnane-3,11,20-trione, 3,20-ethylene glycol diketal of melting point 185-186degrees centigrade.

Analysis.-Calculated for CzsHsaOs: C, 69.09; H, 8.81. Found: C, 69.01;H, 9.02.

Infrared analysis confirmed the postulated structure for17a-hydroxypregnane-3J1,20-trione, 3,20 ethylene glycol diketal.

PREPARATION 2.-17a-HYDRoxYPREeNANE-3,11,20- TRIONE, 3,20-PROPYLENEGLYCOL DIKETAL A solution of 0.50 gram of17oc-hYdl0XYpI6gname-3,11,20-trione, five milliliters of propyleneglycol and fifty milligrams of ortho-chlorobenzenesulfonic acid,dissolved in one hundred milliliters of toluene, is heated under refluxfor ten hours, while the water which is formed in the reaction isremoved by co-distillation with toluene. The cooled solution isneutralized with sodium bicarbonate, washed with water, dried andconcentrated to dryness in vacuo. The crystals of17a-hydroxypregnane-3,11,20-trione, 3,20-propylene glycol diketal arerecrystallized from ethyl acetate.

PREPARATION 3.-17a-HynsoxYPmseNArm-3,11,20- TRIONE, 3,20-PBOPANE-L3-DIOLDIKETAL In essentially the same manner as shown in Preparation 1,17a-hydroxypregnane-3J1,20-trione, 3,20-propane-1,3-diol diketal isprepared by heating 17a-hydroxypregnane-3J1,20-trione withpropane-1,3-diol dissolved in benzene with paratoluenesulfonic acid ascatalyst.

In the same manner as described in Preparations 1 through 3, inclusive,by reacting 17ozhydroxypregnane-3,11,20-trione with an alkanediol,preferably an alkane-l,2-diol or an alkane- 1,3-diol, in the presence ofan acid catalyst in solution, the following compounds may be obtained:17a hydroxypregnane 3,11,20-trione, 3,20-butane-l,2-diol diketal,l'lu-hydroxypregmane-3,11,20-trione, 3,20-butane-l,3-diol diketal, 17hydroxypregnane 3,11,20-trione, 3,20-butane 2,3 diol diketal,l'la-hydroxypregnane- 3,11,20-trione, 3,20pentane-1,2-diol diketal,170chydroxypregnane 3,11,20-trione, 3,20-pentane- 1,3-diol diketal,17a-hydroxypregnane-3J1,20- trione, 3,20-hexane-1,2-diol diketal,1'7oc-hYd1OXY- pregnane 3,11,20 trione, 3,20-hexane-l,3-diol diketal,17a hydroxypregnane 3,11,20-trione, 3,20-heptane-l,2-diol diketal,l'la-hydroxypregnane-3,11,20-trione, 3,20-heptane-1,3-dio1 diketal,l'la-hydroxypregnane-l,11,20-trione, 3,20-

PREPARATION 4.-11B,17u-mHYnRoxYrnEeNANE-3,20- moms, 3,20-ETHYLENE GLYCOLDIKETAL To a solution of five grams of lithium aluminum hydride,dissolved in .600 milliliters of anhydrous ether, was added 29.5 gramsof 17ahydroxypregnane 3,11,20-trione, 3,20-ethylene glycol diketaldissolved in one hundred milliliters of ether and one hundredmilliliters of benzene. The resulting mixture was stirred for one hourat room temperature after which time it was refluxed for another hourand then cooled and hydrolyzed with fifty milliliters of water. Theorganic layer was separated by decantation and the remaining paste wassuspended in water and repeatedly extracted with methylene dichloride.The combined ether and methylene dichloride solutions were concentratedto give a quantitative yield of crystallinelldl'la-dihydroxypregnane-3,20-dione, 3,20-ethylene glycol diketal.Infrared analysis confirmed the postulated structure for11p,l'la-dihydroxypregnane-t,20-dione, 3,20-ethylene glycol diketal.

PREPARATION 5.-11fi,17oL-DIHYDBOXYPREGPLANE-3,20- DIONE, 3,20-PR0PYLENEGLYCOL DIKETAL PREPARATION 6.--11[3,17oL-DIHYDROXYPREGDIANE-3,20- DIONE,3,20-PnorANE-1,3nI0L DIKETAL Following the procedure given inPreparation 4, 11,8,1'la-dihydroxypregnane-3,20-dione, 3,20-propane-1,3-diol diketal is prepared using 17ahydroxypregnane3,11,20-trione, 3,20-propane- 1,3-diol diketal from Preparation 3instead of 17a hydroxypregnane-3,11,20-trione, 3,20-ethylene glycoldiketal.

In the same manner as described in Preparations 4 through 6, inclusive,by reacting a selected 17u-hydroxypregnane-3,11,20-trione, 3,20-alkanediol diketal with a reducing agent such as, for example, lithiumaluminum hydride, lithium borohydride, sodium borohydride, hydrogen inthe presence of catalysts such as Raney nickel, platinum and other likecatalysts in solution, the following representative compounds may beobtained: 11 9,17a-dihydroxypregnane-3,20-dione, 3,20-butane-l,3dioldiketal, 11fi,1'7a-dihydroxypregnane-3,20-dione, 3,20-butane 2,3-dio1diketal, 1118,I'M-dihydroxypregnane-ii,20dione, 3,20- pentane-1,2dio1diketal, 11/3,l'7m-dihydroxypregnane-3,20-dione, 3,20-hexane-1,2-dioldiketal, 11p,17u-dihydroxypregnane-3,ZO-dione, 3,20-heptane- 1,2-dioldiketal, 11{3,17a-dihydroxypregnane-3,20dione, 3,20-octane-1,2-dioldiketal, 113,170 dihydroxypregnane-3,20-dione, 3,20-butane-1,3-dioldiketal, 1lB,l7a-dihydroxypregnane-3,20-dione, 3,20-pentane-1,3-dioldiketal, 11p,17a-dihydroxypregnane-3,ZO-dione, 3,20-hexane-l,3-dioldiketal, 1lp,17u-dihydroxypregnane- 3,20-dione, 3,20-heptane-L3-diol'diketal,-1118,17 ozdihydroxypregnane-=B.20-dione, .3,20-foctane-L3- dioldiketal, and other like cyclic d1ketals.

PREPARATION 7.-'11din-mirror:0xI1 RnsNANE-3,20-

DIONE Twenty-nine'and. one-half grams of 115,170- dihydroxypregnane 3,20dione, 320 ethylene glycol diketal was'dissolved-in 600 milliliters ofacetone and a solution of fourmilliliters of .sulfuric acid in onehundredimilliliters of water was added thereto. The solutionthus-obtained was allowed to stand at room temperature "during a periodof'sixteen hours,,after whichatime the acid was neutralized with:sodium'bicarbonate and the acetone distilled off in vacuo. Theremaining aqueous suspension wasfiltered and the crystalline precipitatewas washed with water and dried. The crudezyield was 19.5 grams (82.7percent). After recrystallization of this material from 200 millilitersof ethyl acetate, 14.04 grams (46.7 percent) of 11 8170edihydroxypregnane- 3,20-dione of melting point 213 to 221 degreescentigrade was obtained.

PREPARATION 8.11fi,17u-DIHYDROXYPREGNANIB-3,20- mom:

One gram of l7a-hydroxypregnane-3,11,20- trione, 3,20-ethylene glycoldiketal, dissolved in 20 milliliters of anhydrous benzene, was added toa solution of one gram of lithium aluminum hydride in 75 milliliters ofanhydrous ether. The reaction mixture was stirred for one hour at roomtemperature and heated under reflux for one hour. Without isolation ofthe intermediate 115,170: dihydroxypregnane 3,20-dione, 3,20- ethyleneglycol diketal, the lithium aluminum complex of the diketal washydrolyzed to give 115.1% dihydroxypregnane-3,20-dione by the slowaddition of one hundred milliliters of dilute hydrochloric acid (fiftypercent) and stirring of the acid mixture for a period of sixteen hoursat room temperature. The organic layer was separated and the acidicsolution extracted repeatedly with 25-milliliter portions of ether. Thecombined washings and organic layer are washed with sodium bicarbonateand water, and then dried over anhydrous sodium sulfate.115,17a-dihydroxypregnane-3,20-dione was recrystallized from ethylacetate and had a melting point of 208 to 212 degrees centigrade.

AnaZysis.-Calculated for Cal-B204: C, 72.38; H, 9.26. Found: C, 72.51;H, 9.09.

PREPARATION 9.11}3,170c-DIHYDROXYPREGNANE-3,20-

moms

Following the procedure given in Preparation 7, 119,17o.-dihydroxypregnane-3,20-dione, 3,20- propylene glycol diketal ishydrolyzed in acetone solution with dilute sulfuric acid to produce11e,17a-dihydroxypregnane-3,20-dione.

Alternatively 11 3,17a-dihydroxypregnane3,20- dione may be obtained from17a-hydroxypregnane-3,1l,20-trione, 3,20-propy1ene glycol diketal byreduction of the diketal with lithium aluminum hydride and hydrolysis ofthe lithium aluminum complex with hydrochloric acid in the manner ofPreparation 8.

PREPARATION 10.11;8,17a-nIHYDRoxYP1tEoNANE-3,20- DIONE Following theprocedure described in Preparation 7,l16,17a-dihydroxypregnane-3,20-dione is prepared by hydrolyzing11p,17u-dihydroxypregnane-3,20-dione, 3,20-propane-1,3-diol diketal,instead of 115,17a-dihydroxypregnane-3,20-di- 6; one, 3;20-:.ethylene:glycol ediketal, imncetone .and.

aqueous sulfuric-acid.

Alternatively, 11,3;1711 dihydroxypregnaneeiwfldione may be obtainedfrom 17a-hydroxyprege nane 3,11,20 trlone, 3,20-propane-L3-diol diketalby reduction of the diketal with lithium aluminum hydride and hydrolysisof the lithium aluminum complex with hydrochloric or: sulfuric acid inthe manner-of Preparation 8.

In the manner shown .in Preparations 7 through 10, 115.1%--dihydroxypregnane*3,20- dione can be obtained by hydrolyzingwith minoral or strong organic acids the following 115,170: dihydroxypregnane-3;20 dione, 3,20- cyclic ketals orthe l l p-lithium-aluminum complexesthereof: 11,3;1-7a-dihydroxypreenane-3,20- dione, 3,20-butane- 1,2-'dioldiketaL' l l'fifl'h-dihydroxypregnane 3,2'0-dione,3,20-'butane'2',3-'diol diketal, l1p,17a-dihydroxypregnane-3.20-dione,3,20 butane-1,3-diol diketal,"11fi;17a dihydroxypregnane-3',20-dione,3;20-'-pentane-1,2-'dio1 diketal, 1 15,170. -ldihydroxypregnane-3,20dione, 3,20-pentane-1,3-diol diketal,11p,17-dihydroxypregnane-3,20-dione, 3,20-hexane-1,2-diol diketal,115,170; dihydroxypregnane 3,20-dione, 3,20-hexane-1,3-diol diketal,11p.17a-dihydroxypregnane-3,20-dione, 3,20-heptane-1,2-diol diketal,115,170; dihydroxypregnane 3,20 dione, 3,20-heptane-L3-diol diketal,11fi,17a-dihydroxypregnane-3,20-dione, 3,20-octane-1,2-diol diketal,115.1% dihydroxypregnane-3,20-dione, 3,20-octane-1,3-diol diketal, andother like cyclic diketals.

Example 1.-4-bromo-11p,17a-dihz/droxypregnane-BJO-dione A solution ofthree grams of 11p,17a-dihydroxypregnane-3,20-dione was dissolved infifty milliliters of acetic acid and thereto 29.2 milliliters of a.solution of bromine in acetic acid containing 0.3096 gram of bromine and0.0275 gram of sodium acetate per milliliter was added under vigorousstirring. The reaction was initiated by ters of a saturated sodiumchloride solution. The crude 4-bromo-1lpJW-dihydroxypregnane-3,20-dione, separated by filtration, weighed 3.18 grams and had amelting point of -197 degrees centigrade after it had beenrecrystallized from acetone. Infrared analysis confirmed the postulatedstructure for 4-bromo-11fi,17a-dihydroxypregnane-3,20-dione.

Analysis. Calculated for 59.01; H, 7.31; 7.46; Br, 18.30.

Example 2.-4-bromo-11p,1h-dihydrowy pregnane-3,20-dione A solution of320 milligrams (2.0 millimoles) of bromine in 3.2 milliliters ofdimethylformamide was added dropwise to a solution of 716 milligrams(2.0 millimoles) of llfl,l7a-dihydroxypregnane-3,20-dione and sixteenmilligrams of para-toluenesulfonic acid in 6.8 milliliters ofdimethylformamide at room temperature. The reaction mixture was stirredduring the addition which required about three hours. After completionof the reaction, water was added and the precipitated4-bromo-1lfi,l7a-dihydroxypreg- C21H31O4Br: C, Br, 18.70. Found: C,59.15; H,

Iiane-3,20-dion'e was" separated by filtration, washed andrecrystallized from acetone.

Infrared analysis confirmed the identity of the compound.

Example 3.-4-chZoro-11p,17a-dihydroa:y-

pregnane-3,20-dione 115,171: dihydroxypregnane 3,20 dione (0.001 mole;0.358 gram) was dissolved in five milliliters of dimethylformamide and afew crystals of para-toluenesulfonic acid were added thereto. A chlorinesolution was prepared by bubbling about 0.9 gram of gaseous chlorineinto 25 milliliters of ice-cold dimethylformamide, resulting in achlorine concentration, as determined by titration, of 1.04 N. To thesolution containing the'steroid, while being stirred, was added dropwise2.3 milliliters (0.00120 mole) of the chlorine solution. Each drop wasallowed to deoolorize before the next was added. The reaction mixturewas then diluted with fifty milliliters of water and cooled. Theprecipitate which was formed was collected, washed with water, anddried. Infrared "analysis confirmed the postulated structure for4-chloro-11fl,17a-dihydroxypregnane-3,20-dione.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described asobvious modifications and equivalents will be apparent to one skilled inthe art, and the inven tion is therefore to be limited only by the scopeof the appended claims.

We claim:

1. A 4 halo 115,170: dihydroxypregnane- 3,20-dione wherein the halogenatom in position 4 has an atomic weight between 35 and 80.

2. 4 bromo 115,17 dihydroxypreg'nane- 3,20-dione.

3. 4 chloro 115,17 dihydroxypregnane- 3,20-dione.

No references cited.

1. A 4 - HALO - 11B,17A - DIHYDROXYPREGNANE3,20-DIONE WHEREIN THEHALOGEN ATOM IN POSITION 4 HAS AN ATOMIC WEIGHT BETWEEN 35 AND 80.